DESCRIPTION: Iron overload, best represented by hereditary hemochromatosis (primary/genetic iron overload) and transfusional hemoglobinopathy (secondary/acquired iron overload), is a well-defined risk factor for several critical diseases, including heart failure, liver cirrhosis, arthritis, diabetes and neurodegenerative diseases. Iron chelators are clinically used to reduce iron burden, but the use of chelators is limited by a number of significant side effects, including hypotension, tachycardia, agranulocytosis, neutropenia, ocular/auditory toxicities, loss of essential nutrients, musculoskeletal-joint pains, gastrointestinal bleeding, hepatic fibrosis and renal failure. Considering tens of millions of people worldwide affected by various types of iron overload disorders, there are urgent needs for a new therapeutic strategy. The primary focus of the DRIVE project is to develop iron chelator-coated ultrasmall nanoparticles (“nanochelators”) in subcutaneously-injectable hydrogel, which allows for a prolonged release of nanochelators that capture plasma iron and are rapidly cleared via urine without non-specific distribution into non-target tissues. The specific aims of the proposed study are 1) to develop subcutaneously-injectable (implantable) hydrogel that contains renally-clearable nanochelators to increase the systemic drug exposure over 2-3 weeks and 2) to characterize the pharmacokinetics, therapeutic efficacy and safety of nanochelators in hydrogel using rodent models of iron overload. Our nanotechnology-based chelation therapy will efficiency decrease iron burden and reduce the risk of iron-induced tissue damage in subjects with iron overload, while minimizing unwanted adverse effects of chelators and increasing patients’ compliance, which together improve clinical outcomes.